Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/60—Salicylic acid; Derivatives thereof

Definitions

• Rational prophylaxis and therapy must be based on the pathogenesis of the respective disease.
• the thrombocytes are of crucial importance, see below. This applies to the initial thrombogenesis in the arterial system as well as to the formation of clotting thrombi in the venous circulation.
• Experimental findings of a more recent kind also indicate that arteriopathies in the broadest sense can be seen as the result of a disturbed relationship between the vessel wall (the endothelium) and the platelets. This state of affairs provides new approaches for corresponding causal therapeutic measures.
• platelet aggregation in vivo is highly likely to occur as a result of the simultaneous activation or release of several endogenous factors [such as the platelet activating factor (PAF), adrenaline, ADP / ATP, lipoxigenase and cyclooxygenase products of arachidonic acid], the effect of one Cyclooxygenase inhibitors (such as acetylsalicylic acid (ASA), sulfinpyrazone) alone are not expected to have a comprehensive therapeutic effect.
• PAF platelet activating factor
• ASA acetylsalicylic acid
• sulfinpyrazone sulfinpyrazone
• the present invention accordingly relates to a novel preparation for the therapy and prophylaxis of thromboembolic disorders, diltiazem and acetylsalicylic acid (ASA) being used as an active ingredient combination, and to the use thereof.
• ASA acetylsalicylic acid
• ASA antithrombotic effect
• the optimal dose is still controversial. The recommendations vary between 300 mg / day and 3 x 500 mg / day or 4 x 325 mg / day.
• ASA causes an irreversible inhibition of cyclooxygenase, an enzyme that produces TX ⁇ 2 in platelets: without TX ⁇ 2 there is no hemostasis (as a desired effect) and no platelet aggregation required for thrombogenesis takes place.
• ASA also inhibits the cyclooxygenase of the intima of the vessels, so that the endogenous aggregation inhibitor PG1 2 cannot be formed; this gives ASA a thrombogenic potency. Since the cyclooxygenase of platelets is more sensitive to ASA and is regenerated more slowly than that of the inner layer of the vessel wall, it is assumed that a certain differentiation of the ASA effects can be achieved via the dose.
• diltiazem a well-known coronary vasodilator
• ASA a well-known coronary vasodilator
• a weak internal platelet aggregation-inhibiting effect of diltiazem would be evident due to the calcium-antagonistic effect, since the activation of platelet phospholipase A 2 , the activation of platelet actomyosin, possibly also that of the platelet-derived growth factor (PDG) Intima are under the control of Ca 2+ ions.
• PDG platelet-derived growth factor
• the combination according to the invention thus represents a real therapeutic advance because of the increased safety and effectiveness.
• An enteral dose unit consists, for example, of 5 to 50 mg of acetylsalicylic acid in combination with 10 to 100 mg of diltiazem and, if appropriate, customary auxiliaries and carriers.
• An enteral dose unit consisting of> 60 mg to 180 mg of diltiazem and 10-300 mg of acetylsalicylic acid is preferred.
• An enteral dose unit of 80 to 100 mg of diltiazem and 50 to 100 mg of acetylsalicylic acid is very particularly preferred.
• Suitable salts are customary acid addition salts of diltiazem with organic or inorganic acids.
• the salts are obtained in the usual way by neutralizing the base with appropriate inorganic or organic acids.
• acids come e.g. Hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, tartaric acid, lactic acid, citric acid, malic acid, salicylic acid, ascorbic acid, malonic acid or succinic acid.
• ASA can advantageously act directly as a salt former, especially because this salt contains the active ingredients in a very good ratio.
• 130 mg of the new diltiazem acetylsalicylate then contain approx. 90 mg of diltiazem active ingredient and 40 mg ASA active ingredient.
• Diltiazem, or an acid addition salt thereof, and acetylsalicylic acid, and diltiazem acetylsalicylate can be used in customary formulations and in mixtures with customary pharmaceutically acceptable carriers or diluents.
• the preparations according to the invention can be administered orally or parenterally in liquid or solid form.
• Water which contains the additives common to injection solutions such as stabilizing agents, solubilizers or buffers, is primarily used as the injection solution.
• the preparations can be in the form of conventional pharmaceutical formulations, such as tablets or capsules. They are prepared by incorporating diltiazem or a pharmacologically acceptable acid addition salt in a manner known per se together with acetylsalicylic acid into a pharmacologically acceptable carrier and, if appropriate, suitable additives.
• Such additives are e.g. Tartrate and citrate buffers, ethanol, complexing agents (such as ethylenediaminetetraacetic acid and its non-toxic salts) and high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation
• solid carriers are e.g. Starch, lactose, mannitol, methyl cellulose, talc, highly disperse silicic acids, higher molecular fatty acids (such as stearic acid), gelatin, agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high molecular polymers (such as polyethylene glycol);
• Preparations suitable for oral administration can optionally contain additional flavorings and / or sweeteners.
• the enterally administered single doses of the new preparation are in the range from 50 to 400 mg.
• Lyophilisates that are only brought into solution shortly before use are considered in the case of injection forms. Lyophilisates are of course dosed correspondingly lower, namely in the range of 5-100 mg per single dose in the same weight ratio as the enteral combinations of diltiazem and ASA.
• the salt has the expected chemical shift in the NMR spectrum, as documented in the following Table II:

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• Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Materials For Medical Uses (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)

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Publications (3)

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• 1986
  • 1986-07-31 DE DE19863626097 patent/DE3626097A1/de not_active Withdrawn
• 1987
  • 1987-07-21 US US07/076,240 patent/US4724266A/en not_active Expired - Fee Related
  • 1987-07-28 PH PH35589A patent/PH24931A/en unknown
  • 1987-07-28 CA CA000543122A patent/CA1285938C/fr not_active Expired - Fee Related
  • 1987-07-28 JP JP62186777A patent/JPS6335522A/ja active Pending
  • 1987-07-30 EP EP87111065A patent/EP0255141B1/fr not_active Expired - Lifetime
  • 1987-07-30 ES ES198787111065T patent/ES2038139T3/es not_active Expired - Lifetime
  • 1987-07-30 KR KR1019870008350A patent/KR880001293A/ko not_active Abandoned
  • 1987-07-30 AT AT87111065T patent/ATE77746T1/de not_active IP Right Cessation
  • 1987-07-30 DE DE8787111065T patent/DE3780095D1/de not_active Expired - Fee Related
  • 1987-07-30 AU AU76282/87A patent/AU592463B2/en not_active Ceased
  • 1987-07-31 ZA ZA875688A patent/ZA875688B/xx unknown
• 1992
  • 1992-07-02 GR GR920401434T patent/GR3005096T3/el unknown

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